Oxazole derivatives and use thereof

ABSTRACT

Oxazole derivatives of the formula (I) ##STR1## wherein one of R and R 1  is a methylsulfonylphenyl, an aminosulfonylphenyl or an alkylaminosulfonylphenyl, and the other is a cycloalkyl having 5 to 7 carbon atoms which is optionally substituted by lower alkyl, a thienyl optionally substituted by lower alkyl or halogen atom or a furanyl optionally substituted by lower alkyl or halogen atom, and R 2  is a lower alkyl, and pharmaceutically acceptable salts thereof. The oxazole derivatives and pharmaceutically acceptable salts thereof have superior antipyretic action, analgesic action, anti-inflammatory action, and particularly, selective inhibitory action on cyclooxygenase-2 (COX-2), and are expected to be useful as an antipyretic agent, an analgesic agent and an anti-inflammatory agent with less side-effects such as disorders in the digestive tract.

This application is a division of Ser. No. 08/849,879 filed Jun. 18,1997, now allowed, which is a national stage of PCT/JP95/02588 filedDec. 15, 1995.

TECHNICAL FIELD

The present invention relates to novel oxazole derivatives. Moreparticularly, the present invention relates to oxazole derivativeshaving antipyretic activity, analgesic activity, anti-inflammatoryactivity, and in particular, selective inhibitory activity againstcyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof andpharmaceutical agents comprising these compounds, which are useful asanti-inflammatory agents causing less side-effects such as disorders inthe digestive tract.

BACKGROUND ART

It has been conventionally known that arachidonic acid metabolites,prostaglandin E₂ (PGE₂), prostaglandin I₂ (PGI₂) and thromboxane B₂(TXB₂) are deeply involved in inflammations. An important enzyme in thisarachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is asynthase which produces prostaglandin H₂ (PGH₂) from arachidonic acidvia prostaglandin G₂ (PGG₂), and includes cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2).

With respect to COX-1, cDNA cloning was performed in 1988 and itsprimary structure and induction by various factors have been clarified[Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165:888-894(1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083:1-17 (1991);DeWitt, D. L.: Biochim. Biophys. Acta, 1083:121-134 (1991)]. On theother hand, the existence of an isozyme of COX-1, namely, COX-2, wassuggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem.,267:21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and humanhave been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA,88:2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem.,266:12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA,89:7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester,lipopolysaccharide (LPS) and the like, and the relationship withinflammation and bronchial asthma has been inferred.

COX-1 systemically and constantly exists in almost all cells and isphysiologically concerned with the generation of prostaglandin (PG)necessary for the functions of, for example, stomach and kidney.Therefore, when COX-1 is inhibited, the biosynthesis of PG byvasodilative PGE₂ and PGI₂, which protect gastric mucosa, is suppressed,and the protective action on the gastric mucosa becomes degraded, as aresult of which ulcer is caused. With regard to a symptom associatedwith a decrease in renal blood flow, in general terms, the renal bloodflow can be increased by promoting the production of vasodilative PGE₂in the body, thereby to appropriately maintain glomerular filtrationrate. However, if the production of such vasodilative PG is suppresseddue to the inhibition of COX-1, the renal blood flow becomes less, sothat a side-effect such as the onset of ischemic acute renalinsufficiency is sometimes caused.

On the other hand, COX-2 exists in particular sites such as monocytes,synovial cells, granulosa cells and intravenous endothelial cells, andis topically expressed when inflammation is caused. It is thereforeconsidered that PG generated by COX-2 is deeply concerned withinflammation and tissue disorders.

Currently, non-steroidal anti-inflammatory drugs (NSAID) such asaspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen andnaproxen have been widely used in clinical situations. Most of theseNSAIDs are anti-inflammatory drugs which selectively inhibitcyclooxygenase (COX) and are associated with side-effects such asdisorders in the digestive tract. Such side-effects are considered to becaused by the fact that they, though certainly selectively inhibit COX,inhibit both COX-1 and COX-2.

It is therefore expected that a selective inhibition of COX-2, which isspecifically induced at the inflammatory sites, would enable provisionof an anti-inflammatory agent free of side-effects such as disorders inthe digestive tract (e.g., ulcer).

There have recently been presented various reports on anti-inflammatorydrugs having selective COX-2 inhibitory activity, which aim at reducingside-effects such as disorders in the digestive tract.

For example, WO94/15932 discloses, as COX-2 inhibitors, 5-memberedcyclic compounds having one hetero atom, such as thiophene, furan andpyrrole, which are specifically exemplified by3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, thesecompounds are characterized by aryl or heteroaryl at the 3-position or4-position of thiophene, and fail to suggest the compounds of thepresent invention.

Moreover, various reports deal with anti-inflammatory drugs havingcyclooxygenase-inhibitory action, prostaglandin synthesis-inhibitoryaction or thromboxane A₂ synthesis-inhibitory action.

For example, Japanese Patent Unexamined Publication No. 141261/1991discloses pyrazole derivatives such as ethyl1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate;Japanese Patent Unexamined Publication No. 183767/1982 disclosesthiazole derivatives such as2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole; and Japanese PatentUnexamined Publication No. 58981/1985 discloses thiazole derivativessuch as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. Thesepublications mention that they are useful as anti-inflammatory drugs,whereas they do not disclose if they have selective inhibitory action onCOX-2 to reduce side-effects, or any suggestion of it.

There are a number of reports on compounds such as those of the presentinvention which include oxazole derivatives or thiazole derivatives.

For example, U.S. Pat. No. 4,632,930 discloses alkyl-aryloxazole such as5-cyclohexyl-4-(4-methylsulfonylphenyl)-α,α-bis(trifluoromethyl)oxazole-2-methanol.Yet, the compounds disclosed therein are effective for hypertension andtheir usefulness as anti-inflammatory drugs or any suggestion to thateffect are not included.

Japanese Patent Application under PCT laid-open under Kohyo No.500054/1984 discloses oxazole derivatives having heteroaryl at one ofthe 4-position and 5-position of oxazole ring, carbon ring aryl at theother position, and carboxy, ester or amidized carboxy via loweralkylene at the 2-position thereof, such as ethyl2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese PatentApplication under PCT laid-open under Kohyo No. 500055/1984 disclosesimidazole derivatives having heteroaryl and/or carbon ring aryl at the4-position or 5-position of imidazole ring and having formyl oracetalized formyl via lower alkylene at the 2-position thereof, such as2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal.As is evident from the disclosure therein, however, these compounds aremainly characterized by the substituent via lower alkylene at the2-position, so that they are not suggestive of the compound of thepresent invention. In addition, these compounds are effective as dermalantiphlogistic or mucosal antiphlogistic for inflammatory dermaldiseases, but do not teach or even suggest that they have selectiveinhibitory action on COX-2.

Japanese Patent Unexamined Publication No. 70446/1993 disclosesN-thiazolylsulfonamide derivatives such asN-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide;and Japanese Patent Unexamined Publication No. 83372/1990 disclosescyclohexylimidazole derivatives such as4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications do notdisclose as to the substitution of the 4-position or 5-position ofthiazole ring or imidazole ring with phenyl substituted byaminosulfonyl, lower alkylaminosulfonyl, lower alkylsulfonylamino orlower alkylsulfonyl.

WO94/27980 discloses oxazole compounds such as2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2inhibitors. However, the compounds described in this publication are,from the overall description in the specification, mainly characterizedby 4-fluorophenyl and 4-methylsulfonylphenyl at the 4-position and5-position of oxazole ring, and do not suggest the compounds havingspecific substituents in combination, as in the present invention. Inaddition, the superior selective inhibition of COX-2 of the presentinvention cannot be envisaged from the compound of this publication.

DISCLOSURE OF THE INVENTION

The present inventors have intensively studied with the aim of providingthe aforementioned novel compound having antipyretic activity, analgesicactivity and anti-inflammatory activity, which is free of side-effectssuch as disorders in the digestive tract. As a result, they have found anovel oxazole derivative having, when compared to known compounds,superior antipyretic activity, analgesic activity, anti-inflammatoryactivity, and particularly, selective inhibitory action on COX-2, andfree of side-effects such as disorders in the digestive tract, whichresulted in the completion of the present invention.

That is, the present invention relates to oxazole derivatives andpharmaceutical agents as shown in the following (1) to (9).

(1) Oxazole derivatives of the formula (I) ##STR2## wherein

one of R and R₁ is a methylsulfonylphenyl, an aminosulfonylphenyl or analkylaminosulfonylphenyl, and the other is a cycloalkyl having 5 to 7carbon atoms which is optionally substituted by lower alkyl, a thienyloptionally substituted by lower alkyl or halogen atom, or a furyloptionally substituted by lower alkyl or halogen atom; and

R₂ is a lower alkyl,

and pharmaceutically acceptable salts thereof.

(2) Oxazole derivatives of the above (1), wherein one of R and R₁ is amethylsulfonylphenyl or an aminosulfonylphenyl, and the other is acyclohexyl or a thienyl optionally substituted by methyl or halogenatom, and R₂ is a methyl, and pharmaceutically acceptable salts thereof.

(3) Oxazole derivatives of the above (2), wherein R₁ is amethylsulfonylphenyl or an aminosulfonylphenyl, R is a cyclohexyl,5-halo-2-thienyl or 5-methyl-2-thienyl, and R₂ is a methyl, andpharmaceutically acceptable salts thereof.

(4) Oxazole derivatives of the above (3), wherein R₁ is amethylsulfonylphenyl, and pharmaceutically acceptable salts thereof.

(5) Oxazole derivatives of the above (3), wherein R₁ is anaminosulfonylphenyl, and pharmaceutically acceptable salts thereof.

(6) Oxazole derivatives of the above (1), which are selected from thegroup consisting of

4-cyclohexyl-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

5-(4-methylsulfonylphenyl)-2-methyl-4-(4-methylcyclohexyl)oxazole,

4-cycloheptyl-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

4-cyclopentyl-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

4-(2-furyl)-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

5-(4-methylsulfonylphenyl)-2-methyl-4-(3-thienyl)oxazole,

5-(4-methylsulfonylphenyl)-2-methyl-4-(2-thienyl)oxazole,

4-(4-methylsulfonylphenyl)-2-methyl-5-(2-thienyl)oxazole,

4-(5-chloro-2-thienyl)-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

5-(5-chloro-2-thienyl)-2-methyl-4-(4-methylsulfonylphenyl)oxazole,

5-(4-methylsulfonylphenyl)-2-methyl-4-(5-methyl-2-thienyl)oxazole,

4-(4-methylsulfonylphenyl)-2-methyl-5-(5-methyl-2-thienyl)oxazole,

5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole,

5-(4-aminosulfonylphenyl)-4-(5-chloro-2-thienyl)-2-methyloxazole, and

4-cyclohexyl-2-methyl-5-(4-methylaminosulfonylphenyl)oxazole,

and pharmaceutically acceptable salts thereof.

(7) Oxazole derivatives of the above (3), which are selected from thegroup consisting of

4-cyclohexyl-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

4-(5-chloro-2-thienyl)-2-methyl-5-(4-methylsulfonylphenyl)oxazole,

5-(4-methylsulfonylphenyl)-2-methyl-4-(5-methyl-2-thienyl)oxazole, and

5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole,

and pharmaceutically acceptable salts thereof.

(8) Cyclooxygenase-2 inhibitors comprising the oxazole derivative of theabove (1) or a pharmaceutically acceptable salt thereof as an activeingredient.

(9) Anti-inflammatory agents comprising the oxazole derivative of theabove (1) or a pharmaceutically acceptable salt thereof as an activeingredient.

As used herein, alkyl means an optionally branched alkyl having 1 to 6carbon atoms, which is specifically exemplified by methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and thelike, with preference given to lower alkyl which is particularlypreferably methyl.

Lower alkyl means an optionally branched alkyl having 1 to 4 carbonatoms, which is specifically exemplified by methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Alkylaminosulfonyl in alkylaminosulfonylphenyl is that whereinaminosulfonyl is substituted by the above-mentioned alkyl andspecifically exemplified by methylaminosulfonyl, ethylaminosulfonyl,propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl,isobutylaminosulfonyl, sec-butylaminosulfonyl, tert-butylaminosulfonyl,pentylaminosulfonyl, isopentylaminosulfonyl, neopentylaminosulfonyl,tert-pentylaminosulfonyl, hexylaminosulfonyl, isohexylaminosulfonyl,neohexylaminosulfonyl and the like. Preferred are aminosulfonylsubstituted by lower alkyl having 1 to 4 carbon atoms, which isspecifically exemplified by methylaminosulfonyl, ethylaminosulfonyl,propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl,isobutylaminosulfonyl, sec-butylaminosulfonyl andtert-butylaminosulfonyl, and particularly preferred ismethylaminosulfonyl.

Cycloalkyl means a cycloalkyl having 5 to 7 carbon atoms, which isspecifically exemplified by cyclopentyl, cyclohexyl and cycloheptyl.Preferred is cyclohexyl.

Halogen atom means chlorine atom, bromine atom, fluorine atom and thelike.

Pharmaceutically acceptable salt may be any as long as it forms anon-toxic salt with the oxazole derivative of the above formula (I).Alkali metal salts such as sodium salt and potassium salt, alkalineearth metal salts such as magnesium salt and calcium salt, ammoniumsalt, organic base salts such as trimethylamine salt, triethylaminesalt, pyridine salt, picoline salt, dicyclohexylamine salt andN,N'-dibenzylethylenediamine salt, and amino acid salts such as lysinesalt and arginine salt are among the examples. It may be a hydrate asthe case demands.

The oxazole derivative of the present invention wherein either R or R₁,particularly R₁, is methylsulfonylphenyl or aminosulfonylphenyl, and theother is cyclohexyl or thienyl substituted by chlorine atom or methyl,and R₂ is methyl is preferable.

The compound of the present invention has superior antipyretic activity,analgesic activity and anti-inflammatory activity, as well asselectively inhibits COX-2. Hence, the compound is expected to make atherapeutic drug free of side-effects such as digestive tract disorders.

When the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof is used as a pharmaceuticalpreparation, it is generally admixed with pharmacologically acceptablecarriers, excipients, diluents, extenders, disintegrators, stabilizers,preservatives, buffers, emulsifying agents, aromatics, colorings,sweeteners, thickeners, flavors, solubilizers and other additives knownper se, such as water, vegetable oil, alcohol such as ethanol and benzylalcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydratessuch as lactose and starch, magnesium stearate, talc, lanolin andpetrolatum, and formulated into tablets, pills, powders, granules,suppositories, injections, eye drops, liquids, capsules, troches,aerosols, elixirs, suspensions, emulsions, syrups and the like, whichcan be administered orally or parenterally.

While the dose varies depending on the kind and severity of the disease,compound to be administered, administration route, and age, sex, bodyweight etc. of patients, 0.1 mg-1,000 mg, particularly 1 mg-300 mg ofcompound (I) is generally administered orally to an adult per day.

The compounds of the present invention can be prepared, for example, bythe following methods. It is needless to say that the method forpreparing the compounds of the present invention is not limited to thesemethods. ##STR3## wherein R₂ ' is lower alkyl which is different fromR₂, X is halogen atom, X₁ is halogen atom or hydroxy, and R, R₁ and R₂are as defined above.

Step 1

Compound (IV) can be synthesized by reacting compound (II) with compound(III) in the presence of a metal such as zinc and magnesium in an inertsolvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran,methylene chloride, benzene and toluene at room temperature. In thiscase, a catalyst such as palladium(O) complex and copper(I) complex maybe added.

Step 2

Compound (V) can be synthesized by refluxing compound (IV) under heatingin the presence of a complex such as lead tetraacetate and manganeseacetate, in lower alkanecarboxylic acid such as acetic acid, propionicacid and benzoic acid corresponding to R₂ COOH wherein R₂ is as definedabove and, where necessary, a solvent such as benzene.

Step 3

Compound (I) can be synthesized by refluxing compound (V) under heatingin the presence of ammonium salt (e.g., lower alkanecarboxylic acidammonium such as ammonium acetate and ammonium formate, and inorganicacid ammonium such as ammonium carbonate) in an acidic solvent such aslower alkanecarboxylic acid (e.g., formic acid, acetic acid andpropionic acid). In this reaction, when R or R₁ is aromatic heterocycle,isomers may be produced wherein the 4-position R and the 5-position R₁are reversed.

Compound (I) can be also synthesized by the following route.

Step 4 wherein X₁ is hydroxy

This step, Step 5 and Step 6 are advantageous when R₂ (e.g., methyl) isconverted to other R₂ (e.g., R₂ ' such as ethyl).

When X₁ is hydroxy, compound (VI) can be synthesized by reactingcompound (V) in the presence of a base such as potassium carbonate,lithium hydroxide, sodium hydroxide and potassium hydroxide in anorganic solvent such as methanol, ethanol and dioxane, water or a mixedsolvent thereof from under cooling to under heating.

Step 5

Compound (V') can be synthesized by reacting compound (VI) and compound(VII') in pyridine, or in the presence of a base such as triethylaminein an organic solvent such as methylene chloride and chloroform, fromunder cooling to under heating.

Step 6

Compound (I') can be obtained by treating compound (V') in the samemanner as in Step 3. When a compound wherein either R or R₁ isaminosulfonylphenyl is desired, the compound can be prepared from acorresponding compound having methylsulfonylphenyl by a known method.

Compounds (VI) and (V) can be also synthesized by the following Steps 7and 8.

Step 7 wherein X₁ is halogen atom or hydroxy

Compound (VI) can be synthesized by reacting compound (IV) in thepresence of a halogenizing agent such as bromine, chlorine andN-bromosuccinimide in an inert solvent such as acetic acid,1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylenechloride, benzene and toluene, or by oxidizing with an oxidizing agentsuch as iodobenzene diacetate. Alternatively, the hydroxy compound canbe also synthesized by treating the aforementioned halogenized compoundof compound (VI) in an inert solvent such as 1,2-dimethoxyethane,dioxane, ether, tetrahydrofuran, benzene and toluene using an aqueousbasic solution. ##STR4## wherein R, R₁, R₂ and X₁ are as defined above.

Step 8

Compound (V) can be synthesized by reacting compound (IV) with compound(VII) in the presence of a metal complex such as manganese acetate in aninert solvent such as benzene.

When a compound wherein either R or R₁ is alkylaminosulfonylphenyl oraminosulfonylphenyl is desired, the compound (IV) can be alsosynthesized from compound (X) wherein one of R₃ and R₄ ismethoxysulfonylphenyl by the following steps. ##STR5## wherein one of R₃and R₄ is methoxysulfonylphenyl, and the other is cycloalkyl optionallysubstituted by lower alkyl, or thienyl or furyl optionally substitutedby lower alkyl or halogen atom, and R, R₁ and X are as defined above.

Step 9

Compound (X) can be synthesized in the same manner as in Step 1, usingcompound (VIII) and compound (IX).

Step 10

The compound (IV) can be synthesized by refluxing compound (X) underheating in pyridine, or in the presence of sodium iodide, potassiumiodide, lithium iodide and the like in an organic solvent such asacetone and tetrahydrofuran, after which reacting the obtained compoundwith thionyl chloride or oxalyl chloride under heating, and thenreacting the resulting product in the presence of aqueous ammonia oralkylamine, or a base such as sodium acetate and ammonium salt such asalkylamine hydrochloride, in an organic solvent such as tetrahydrofuran,ether, toluene, benzene, methylene chloride and dioxane, from undercooling to under heating.

Compound (I) can be also synthesized by the following route. ##STR6##wherein either R' or R₁ ' is phenyl, the other is cycloalkyl which maybe substituted by lower alkyl, or thienyl or furyl, which may besubstituted by lower alkyl or halogen atom, and R, R₁, R₂ and X are asdefined above.

Step 11

Compound (IV') can be synthesized by reacting compound (II') andcompound (III') in the presence of a metal such as zinc and magnesium inan inert solvent such as 1,2-dimethoxyethane, dioxane, ether,tetrahydrofuran, methylene chloride, benzene and toluene at roomtemperature. In this case, a catalyst such as palladium(O) complex andcopper(I) iodide may be added.

Step 12

Compound (XI) can be synthesized by refluxing under heating compound(IV') and hydroxylamine hydrochloride in the presence of a base such assodium acetate, sodium hydroxide and potassium carbonate in an organicsolvent such as methanol, ethanol and tetrahydrofuran, water or a mixedsolvent thereof.

Step 13

Compound (XII) can be synthesized by reacting compound (XI) in thepresence of an acylating agent such as acetic anhydride and acetylchloride, in pyridine, or in the presence of a base such astriethylamine in an organic solvent such as methylene chloride andchloroform, from under cooling to under heating.

Step 14

Compound (XIII) can be synthesized by refluxing compound (XI) underheating in an acidic solvent such as formic acid and acetic acid. Inthis case, a dehydrating agent such as magnesium sulfate and sodiumsulfate may be added.

Step 15

Compound (I) can be synthesized by reacting compound (XIII) in thepresence of a chlorosulfonylating agent such as chlorosulfonic acid inan organic solvent such as chloroform and methylene chloride, or withoutsolvent, and reacting, when aminosulfonylation oralkylaminosulfonylation is desired, the resulting product in thepresence of aqueous ammonia, alkylamine or a base such as sodium acetateand ammonium salt such as alkylamine hydrochloride in an organic solventsuch as tetrahydrofuran, ether, toluene, benzene, methylene chloride anddioxane from under cooling to under heating. When alkylsulfonation is tobe carried out, the method described in J. Org. Chem., 56:4974-4976(1991) can be used for the synthesis.

The compound (I) thus obtained can be isolated and purified by a knownmethod for separation and purification, such as concentration,concentration under reduced pressure, solvent extraction, crystalprecipitation, recrystallization and chromatography.

The present invention is described in more detail in the following byillustrative Examples and Experimental Examples, to which the presentinvention is not limited.

EXAMPLE 1

Synthesis of 4-cyclohexyl-2-methyl-5-(4-methylsulfonylphenyl)-oxazole(formula (I); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ =methyl)

Step 1) Cyclohexyl 4-methylsulfonylbenzyl ketone (formula (IV);R=cyclohexyl, R₁ =4-methylsulfonylphenyl)

To a solution of cyclohexanecarbonyl chloride (6.18 g),tetrakis(triphenylphosphine)palladium (2.32 g) and zinc powder (3.42 g)in 1,2-dimethoxyethane (200 ml) was dropwise added a solution of4-methylsulfonylbenzyl bromide (10.00 g) in 1,2-dimethoxyethane (100 ml)at room temperature, and the mixture was stirred for 2 hours. Theinsoluble matter was removed by filtration and the filtrate wasconcentrated. Then, ethyl acetate was added, and the mixture was washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated, and ethyl acetate and diisopropyl ether wereadded, whereby 5.42 g of the title compound was obtained as a whitesolid (yield 48%).

Step 2) 2-Cyclohexyl-1-(4-methylsulfonylphenyl)-2-oxoethyl acetate(formula (V); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ =methyl)

To a solution of the compound (1.48 g) synthesized in the above Step 1)in acetic acid (20 ml) was added lead tetraacetate (2.5 g), which wasfollowed by refluxing under heating for 3 hours and evaporation of thesolvent. Ethyl acetate was added to the residue and the mixture waswashed with water, saturated aqueous sodium hydrogencarbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=5:2) to give0.52 g of the title compound as a white solid (yield 29%).

Step 3) 4-Cyclohexyl-2-methyl-5-(4-methylsulfonylphenyl)oxazole (formula(I); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ =methyl)

A solution of the compound (0.52 g) obtained in the above Step 2) andammonium acetate (0.29 g) in acetic acid (10 ml) was refluxed underheating for 3 hours and the solvent was evaporated. The residue wasdissolved in ethyl acetate, and the solution was washed with water,saturated aqueous sodium hydrogencarbonate solution and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=7:2) to give 0.38 g of the title compoundas a white solid (yield 77%).

EXAMPLE 2

Synthesis of5-(4-methylsulfonylphenyl)-2-methyl-4-(5-methyl-2-thienyl)oxazole (A)(formula (I); R=5-methyl-2-thienyl, R₁ =4-methylsulfonylphenyl, R₂=methyl) and4-(4-methylsulfonylphenyl)-2-methyl-5-(5-methyl-2-thienyl)oxazole (B)(formula (I); R=4-methylsulfonylphenyl, R₁ =5-methyl-2-thienyl, R₂=methyl)

Step 3) A solution of1-(4-methylsulfonylphenyl)-2-(5-methyl-2-thienyl)-2-oxoethyl acetate(0.80 g) obtained according to a method similar to the methods of theabove Example 1, Step 1) and Step 2) and ammonium acetate (1.02 g) inacetic acid (15 ml) was refluxed under heating for 4 hours, and thesolvent was evaporated. The residue was separated and purified by silicagel column chromatography (developing solvent; hexane:ethyl acetate=1:1)to give 0.26 g of the title compound (A) as a white solid (yield 34%)and 0.02 g of the title compound (B) as a white solid (yield 3%).

EXAMPLE 3

Synthesis of 4-cyclohexyl-2-ethyl-5-(4-methylsulfonylphenyl)oxazole(formula (I'); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ '=ethyl)

Step 4) 2-Cyclohexyl-1-(4-methylsulfonylphenyl)-2-oxoethanol (formula(VI); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, X₁ =hydroxy)

A solution of 2-cyclohexyl-1-(4-methylsulfonylphenyl)-2-oxoethyl acetate(0.34 g) obtained according to a method similar to the methods ofExample 1, Step 1) and Step 2) and 1N lithium hydroxide (1.0 ml) inmethanol (2 ml) and dioxane (1 ml) was stirred under ice-cooling for 0.5hour. 5% Citric acid was added and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated to give 0.30 g of a crude product of the title compound.

Step 5) 2-Cyclohexyl-1-(4-methylsulfonylphenyl)-2-oxoethyl propionate(formula (V'); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ '=ethyl)

The crude product (0.20 g) obtained in the above Step 4) was dissolvedin pyridine (1.5 ml), and propionyl chloride (0.10 ml) was added underice-cooling. The mixture was stirred at room temperature for 4 hours andthe solvent was evaporated. Ethyl acetate was added to the residue, andthe mixture was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=2:1) to give 0.12 g of the title compound as awhite solid (yield 50%).

Step 6) 4-Cyclohexyl-2-ethyl-5-(4-methylsulfonylphenyl)oxazole (formula(I'); R=cyclohexyl, R₁ =4-methylsulfonylphenyl, R₂ '=ethyl)

In the same manner as in Example 1, Step 3), 0.06 g of the titlecompound was obtained as a white solid (yield 63%) from the compoundobtained in the above Step 5).

EXAMPLES 4-12

In the same manner as in Examples 1 to 3, the compounds of Tables 1 to 5were obtained. In the Tables, Me means methyl, Et means ethyl and Phmeans phenyl.

                                      TABLE 1                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________      1                                                                                                                                     110R7##                                                                     ° C.                                                                   white  crystals                                                               CDCl.sub.3 300MHz                                                              1.20-1.98(10H,                                                               m)  2.51(3H, s)                                                               2.82(1H, m)                                                                   3.08(3H, s)                                                                   7.72(2H, d,                                                                   J=8.4Hz)                                                                      7.98(2H, d,                                                                   J=8.4Hz) neat                                                                 2927  2853  1602                                                              1578  1308  1152                                                              FAB+  320(MH.sup.+                                                            ) C.sub.17                                                                    H.sub.21 NO.sub.3                                                             S  calculated  C                                                              63.92%  H 6.63%                                                               N 4.39%  found  C                                                             63.83%  H 6.69%                                                               N 4.19%                  - 2 (A)                                                                                                                              155° C.                                                              pale-  yellow                                                                 crystals CDCl.sub.                                                            3 300MHz                                                                      2.52(3H, d,                                                                   J=0.74Hz)                                                                     2.55(3H, s)                                                                   3.09(3H, s)                                                                   6.72(1H, dq,                                                                  J=1.1, 3.3Hz)                                                                 7.15(1H, d,                                                                   J=3.7Hz)                                                                      7.9-7.96(4H, m)                                                               KBr  3428  2998                                                               2918  1599  1584                                                              FAB+  334(MH.sup.+                                                            ) C.sub.16                                                                    H.sub.14 NO.sub.3                                                             S.sub.2  calculate                                                            d  C 57.64%  H                                                                4.53%  N 4.20%                                                                found  C 57.72%                                                               H 4.47%  N 4.23%                                                                - 2 (B)                                                                       oily  substance                                                             CDCl.sub.3 300MHz                                                              2.52(3H, s)                                                                  2.54(3H, s)                                                                   3.08(3H, s)                                                                   6.74(1H, d,                                                                   J=3.4Hz)                                                                      7.12(1H, d,                                                                   J=3.4Hz)                                                                      7.94(3H, s) neat                                                              2924  1601  1310                                                              FAB+  334(MH.sup.+                                                            )                     __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________      3                                                                                                                                     114R10##                                                                    ° C.                                                                   white  crystals                                                               CDCl.sub.3 300MHz                                                              1.38(3H, m)                                                                  1.38(3H, t,                                                                   J=7.7Hz)                                                                      1.7-1.9(7H, m)                                                                2.83(1H, m)                                                                   2.85(2H, q,                                                                   J=7.7Hz)                                                                      7.72(2H, d,                                                                   J=8.8Hz)                                                                      7.99(2H, d,                                                                   J=8.8Hz) KBr                                                                  2933  1612  1576                                                              1300  1147 FAB+                                                               334(MH.sup.+)                                                                 C.sub.18 H.sub.23                                                             NO.sub.3 S                                                                    calculated  C                                                                 64.84%  H 6.95%                                                               N 4.20%  found  C                                                             64.99%  H 7.07%                                                               N 4.13%                  - 4                                                                                                                                  125-129°                                                             C.  white  solid                                                              CDCl.sub.3 300MHz                                                              0.94(3H, d,                                                                  J=6.5Hz)                                                                      0.90-2.10(9H, m)                                                              2.52(3H, s)                                                                   2.77(1H, m)                                                                   3.09(3H, s)                                                                   7.72(2H, d,                                                                   J=8.5Hz)                                                                      7.99(2H, d,                                                                   J=8.5Hz) neat                                                                 2924  2858  1604                                                              1577  1310  1152                                                              FAB+  334(MH.sup.+                                                            )                        - 5                                                                                                                                  121-124°                                                             C.  white  solid                                                              CDCl.sub.3 300MHz                                                              1.71(3H, brs)                                                                1.76-2.28(5H, m)                                                              2.42(1H, m)                                                                   2.52(3H, s)                                                                   3.02(1H, m)                                                                   3.08(3H, s)                                                                   5.48(1H, brs)                                                                 7.73(2H, d,                                                                   J=8.6Hz)                                                                      7.98(2H, d,                                                                   J=8.6Hz) neat                                                                 2925  1603  1578                                                              1313  1152 FAB+                                                               332(MH.sup.+)         __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________      6                                                                                                                                     99TR13##                                                                    ° C.                                                                   white  solid                                                                  CDCl.sub.3 300MHz                                                              1.60-2.05(8H, m)                                                              2.51(3H, s)                                                                  3.07(3H, s)                                                                   3.25(1H, m)                                                                   7.74(2H, d,                                                                   J=8.6Hz)                                                                      7.98(2H, d,                                                                   J=8.6Hz) neat                                                                 2953  2868  1601                                                              1579  1310  1152                                                              FAB+  306(MH.sup.+                                                            ) C.sub.16                                                                    H.sub.19 NO.sub.3                                                             S  calculated  C                                                              62.93%  H 6.27%                                                               N 4.59%  found  C                                                             63.02%  H 6.40%                                                               N 4.38%                  - 7                                                                                                                                  115-116°                                                             C.  white  solid                                                              CDCl.sub.3 300MHz                                                              1.5-1.7(6H, m)                                                               1.88(6H, m)                                                                   2.51(3H, s)                                                                   2.98(1H, m)                                                                   3.08(3H, s)                                                                   7.72(2H, d,                                                                   J=8.4Hz)                                                                      7.99(2H, d,                                                                   J=8.4Hz) KBr                                                                  2925  2856  1611                                                              1577  1304  1151                                                              FAB+  334(MH.sup.+                                                            )  333(M.sup.+)                                                               C.sub.18 N.sub.23                                                             NO.sub.3 S                                                                    calculated  C                                                                 64.84%  H 6.95%                                                               N 4.20%  found  C                                                             65.11%  H 7.16%                                                               N 4.24%                  - 8                                                                                                                                  109-113°                                                             C.  white  solid                                                              CDCl.sub.3 300MHz                                                              2.57(3H, s)                                                                  3.09(3H, s)                                                                   6.55(1H, dd,                                                                  J=1.8, 3.4Hz)                                                                 6.87(1H, dd,                                                                  J=0.7, 3.4Hz)                                                                 7.50(1H, dd,                                                                  J=0.7, 1.8Hz)                                                                 7.98(2H, d,                                                                   J=8.7Hz)                                                                      8.04(2H, d,                                                                   J=8.7Hz) neat                                                                 1598  1406  1305                                                              1151 FAB+                                                                     304(MH.sup.+)         __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________       9                                                                                                                                    142° C.                                                              pale-  purple                                                                 plate  crystals                                                               CDCl.sub.3 300MHz                                                              2.57(3H, s)                                                                  3.08(3H, s)                                                                   7.26(1H, dd,                                                                  J=1.30, 4.89Hz)                                                               7.38(1H, dd,                                                                  J=2.98, 5.00Hz)                                                               7.62(1H, dd,                                                                  J=1.30, 3.00Hz)                                                               7.81(2H, dt,                                                                  J=8.66, 1.81Hz)                                                               7.93(2H, dt,                                                                  J=8.61, 1.97Hz)                                                               KBr  3448  1599                                                               1577  1405  1307                                                              FAB+  320(MH.sup.+                                                            ) C.sub.15                                                                    H.sub.13 NO.sub.3                                                             S.sub.2  calculate                                                            d  C 56.41%  H                                                                4.10%  N 4.39%                                                                found  C 56.17%                                                               H - # 4.07%  N                                                                4.35%                    - 10 (A)                                                                                                                             131° C.                                                              yellow  crystals                                                              CDCl.sub.3 300MHz                                                              2.55(3H, s)                                                                  3.09(3H, s)                                                                   6.87(1H, d,                                                                   J=4.0Hz)                                                                      7.13(1H, d,                                                                   J=4.0Hz)                                                                      7.89(2H, d,                                                                   J=8.4Hz)                                                                      7.97(2H, d,                                                                   J=8.6Hz) KBr                                                                  3440  2983  2905                                                              1597  1584 FAB+                                                               354(M.sup.+)                                                                  C.sub.15 H.sub.12                                                             ClNO.sub.3                                                                    S.sub.2  calculate                                                            d  C 50.91%  H                                                                3.42%  N 3.96%                                                                found  C 50.95%                                                               H 3.42%  N 3.87%                                                                - 10 (B)                                                                      oily  substance                                                             CDCl.sub.3 300MHz                                                              2.54(3H, s)                                                                  3.08(3H, s)                                                                   6.90(1H, d,                                                                   J=3.9Hz)                                                                      7.09(1H, d,                                                                   J=4.0Hz)                                                                      7.88-7.98(4H, m)                                                              neat  2926  1601                                                              1440  1403  1316                                                              FAB+  354(M.sup.+)    __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________      11 (A)                                                                                                                                107R19##                                                                    ° C.                                                                   white  powder                                                                 CDCl.sub.3 300MHz                                                              2.57(3H, s)                                                                  3.08(3H, s)                                                                   7.07(1H, dd,                                                                  J=3.7, 5.1Hz)                                                                 7.35(1H, dd,                                                                  J=3.6, 1.2Hz)                                                                 7.40(1H, dd,                                                                  J=5.1, 1.1Hz)                                                                 7.85-7.97(4H, m)                                                              KBr  3439  1599                                                               1577  1308 FAB+                                                               320(MH.sup.+)                                                                 C.sub.15 H.sub.13                                                             NO.sub.3 S.sub.2                                                              calculated  C                                                                 56.41%  H 4.10%                                                               N 4.39%  found  C                                                             56.37%  H 4.00%                                                               N 4.31%                  - 11 (B)                                                                                                                             oily  substance                                                             CDCl.sub.3 300MHz                                                              2.56(3H, s)                                                                  3.08(3H, s)                                                                   7.09(1H, dd,                                                                  J=2.7, 3.7Hz)                                                                 7.33(1H, dd,                                                                  J=0.7, 2.9Hz)                                                                 7.43(1H, dd,                                                                  J=0.7, 3.7Hz)                                                                 7.94(4H, s) neat                                                              3105  3020  2927                                                              1602  1311 FAB+                                                               320(MH.sup.+)                                                                   - 12                                                                          234-236°                                                             C.  white                                                                     crystals CDCl.sub.                                                            3 300MHz                                                                      1.41(3H, m)                                                                   1.8-1.9(7H, m)                                                                2.91(1H, m)                                                                   3.10(3H, s)                                                                   7.48(3H, m)                                                                   7.83(2H, d)                                                                   8.03(2H, d)                                                                   8.11(2H, m) KBr                                                               2930  1600  1301                                                              1147 FAB+                                                                     382(MH.sup.+)                                                                 C.sub.22 H.sub.23                                                             NO.sub.3 S                                                                    calculated  C                                                                 69.26%  H 6.08%                                                               N 3.67%  found  C                                                             69.29%  H 6.16%                                                               N 3.71%               __________________________________________________________________________

EXAMPLE 13

Synthesis of5-(4-aminosulfonylphenyl)-4-(5-chloro-2-thienyl)-2-methyloxazole(formula (I); R=5-chloro-2-thienyl, R₁ =4-aminosulfonylphenyl, R₂=methyl)

Step 9) Methyl 4-(5-chloro-2-thenoylmethyl)phenylsulfonate (formula (X);R₃ =4-methoxysulfonylphenyl, R₄ =5-chloro-2-thienyl) In the same manneras in Example 1, Step 1) and using methyl p-bromomethylbenzenesulfonateand 5-chloro-2-thenoyl chloride, the title compound was obtained.

Step 10) 4-(5-Chloro-2-thenoylmethyl)phenylsulfonamide (formula (IV);R=5-chloro-2-thienyl, R₁ =aminosulfonylphenyl)

The compound (3.32 g) obtained in the above Step 9) was refluxed underheating in pyridine (15 ml) for 10 hours, and pyridine was evaporated.Thionyl chloride (20 ml) was added to the residue and the mixture washeated at 100° C. for 7 hours. Thionyl chloride was evaporated anddioxane (40 ml) and 28% aqueous ammonia (18 ml) were added to theresidue, which was followed by stirring at room temperature for 1.5hours. Then, the mixture was extracted with ethyl acetate, and theextract was washed with saturated brine, and dried over magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography (developing solvent; hexane:ethylacetate=1:2) to give 116 mg of the title compound.

Step 2) 1-(4-Aminosulfonylphenyl)-2-(5-chloro-2-thienyl)-2-oxoethylacetate (formula (V); R=5-chloro-2-thienyl, R₁ =aminosulfonylphenyl, R₂=methyl)

In the same manner as in Example 1, Step 2) and using the compound (116mg) obtained in the above Step 10), 113 mg of the title compound wasobtained (yield 82%).

Step 3) 5-(4-Aminosulfonylphenyl)-4-(5-chloro-2-thienyl)-2-methyloxazole(formula (I); R=5-chloro-2-thienyl, R₁ =4-aminosulfonylphenyl, R₂=methyl)

In the same manner as in Example 1, Step 3) and using the compound (113mg) obtained in the above Step 2), 6 mg of the title compound wasobtained as a white powder (yield 6%).

EXAMPLE 14

Synthesis of 5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole(formula (I); R=cyclohexyl, R₁ =4-aminosulfonylphenyl, R₂ =methyl)

Step 11) Cyclohexyl benzyl ketone (formula (IV'); R₁ =cyclohexyl, R₁'=phenyl)

To a solution of tetrakis(triphenylphosphine)palladium (2.37 g) and zincpowder (26.81 g) in 1,2-dimethoxyethane (50 ml) was added a solution ofcyclohexanecarbonyl chloride (30.00 g) in 1,2-dimethoxyethane (50 ml),and the mixture was stirred at room temperature under a nitrogenatmosphere for 30 minutes. A solution of benzyl bromide (35.00 g) in1,2-dimethoxyethane (100 ml) was dropwise added under ice-cooling withstirring at a rate to keep the temperature of the reaction mixture at10-15° C., and the mixture was stirred under ice-cooling for 30 minutesand at room temperature for one hour. The insoluble matter was removedby filtration and the filtrate was concentrated. Then, the residue wasdissolved in ethyl acetate (200 ml), and the solution was washed twicewith 1N hydrochloric acid (150 ml) and then with saturated aqueoussodium hydrogencarbonate solution (100 ml) and saturated brine (50 ml),and dried over anhydrous sodium sulfate. The solvent was evaporated togive 43.06 g of a crude product as an oil.

Step 12) Cyclohexyl benzyl ketone oxime (formula (XI); R'=cyclohexyl, R₁'=phenyl)

The compound (43.00 g) synthesized in the above Step 11), hydroxylaminehydrochloride (16.20 g) and sodium acetate (26.20 g) were dissolved inethanol (200 ml), and the solution was refluxed under heating for 2hours. Then, the solvent was evaporated and ethyl acetate (400 ml) andwater (100 ml) were added to the residue. The organic layer was washedwith water (200 ml) and saturated brine (100 ml), and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and recrystallization from ethanol (30 ml) gave 25.2 g of thetitle compound (yield 57%).

Step 13) Cyclohexyl benzyl ketone O-acetyloxime (formula (XII);R'=cyclohexyl, R₁ '=phenyl, R₂ =methyl)

To a solution of the compound (24.40 g) obtained in the above Step 12)in pyridine (75 ml) was added acetic anhydride (16 ml) at roomtemperature, and the mixture was stirred for one hour. Then, the solventwas concentrated under reduced pressure and the residue was dissolved inethyl acetate (300 ml). The solution was washed with 10% hydrochloricacid (100 ml) and then with water (100 ml), saturated aqueous sodiumhydrogencarbonate solution (100 ml) and saturated brine (50 ml). Theorganic layer was dried over anhydrous sodium hydrochloride. The solventwas evaporated under reduced pressure to quantitatively give the titlecompound as an oil.

Step 14) 4-Cyclohexyl-2-methyl-5-phenyloxazole (formula (XIII);R=cyclohexyl, R₁ '=phenyl, R₂ =methyl)

A solution of the compound (30.00 g) obtained in the above Step 13) andsodium acetate (15.00 g) in acetic acid (150 ml) was refluxed underheating for 4 hours. Then, ethyl acetate (600 ml) and water (150 ml)were added to the residue to separate the organic layer. The organiclayer was washed with water (200 ml), saturated aqueous sodiumhydrogencarbonate solution (200 ml) and saturated brine (100 ml), anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the residue was distilled under reduced pressure (9torr) to give 15.2 g of the title compound (yield 54%).

Step 15) 5-(4-Aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole (formula(I); R=cyclohexyl, R₁ =4-aminosulfonylphenyl, R₂ =methyl)

To the compound (14.00 g) obtained in the above Step 14) was dropwiseadded chlorosulfonic acid (25 ml) with stirring under ice-cooling, andthe mixture was heated at 60° C. for 4 hours. After cooling to the roomtemperature, the reaction mixture was dropwise added to ice water (350ml) with stirring. The precipitated solid was collected by filtrationand dried under reduced pressure at 50° C. for 15 hours to give 15.42 gof a crude product as a pale-brown solid.

Then, this crude product (7.00 g) was added to tetrahydrofuran (40 ml),and 28% aqueous ammonia was added at room temperature with stirring.After stirring at room temperature for one hour, the mixture wasconcentrated under reduced pressure and the residue was dissolved inethyl acetate. The solution was washed with water (35 ml) and saturatedbrine (30 ml), and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was recrystallizedfrom ethanol (40 ml) to give 3.31 g of the title compound as whitecrystals (yield 50%).

EXAMPLE 15

Synthesis of4-cyclohexyl-2-methyl-5-(4-methylaminosulfonylphenyl)oxazole (formula(I); R=cyclohexyl, R₁ =4-methylaminosulfonylphenyl, R₂ =methyl)

Step 15) 4-Cyclohexyl-2-methyl-5-(4-methylaminosulfonylphenyl)oxazole(formula (I); R=cyclohexyl, R₁ =4-methylaminosulfonylphenyl, R₂ =methyl)

To a compound (1.00 g) obtained in the same manner as in the aboveExample 14, Steps 11) to 14) was dropwise added with stirring underice-cooling chlorosulfonic acid (3 ml), and the mixture was heated at60° C. for 4 hours. After cooling to the room temperature, the reactionmixture was dropwise added to ice water (100 ml) with stirring. Theprecipitated solid was collected by filtration and dried under reducedpressure at 50° C. for 15 hours to give 2.07 g of a crude product as apale-brown solid.

Then, this crude product (300 mg) was added to a solution of methylamineacetate (300 mg), triethylamine (0.6 ml) in a mixed solvent of dioxane(2 ml) and water (5 ml), and the mixture was stirred at room temperaturefor one day. Ethyl acetate was added and the organic layer was washedwith water, 1N citric acid and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated and isopropyl ether was addedto the residue. A white solid was collected by filtration to give 100 mgof the title compound (yield 50%).

Note that the above-mentioned Examples 3, 5 and 12 are ReferenceExamples.

                                      TABLE 6                                     __________________________________________________________________________                                                            Elemental                                                                      Ex. Compound                                                                 m.p. .sup.1 H NMR                                                             (δ) ppm IR                                                              cm.sup.-1 MS                                                                  analysis              __________________________________________________________________________      13                                                                                                                                    white  powder                                                               CDCl                                                                          .sub.3 300MHz                                                                 2.55(3H, s)                                                                   4.80(3H, s)                                                                   6.87(1H, d,                                                                   J=3.91Hz)                                                                     7.12(1H, d,                                                                   J=3.91Hz)                                                                     7.85(2H, d,                                                                   J=8.55Hz)                                                                     7.96(2H, d,                                                                   J=8.51Hz) neat                                                                3262  2925  1707                                                              1583  1443  1336                                                              1103  758 FAB+                                                                354.9  FAB-                                                                   354.9                    - 14                                                                                                                                 184.5-                                                                      186.5° C.                                                              white  crystals                                                               CDCl.sub.3 300MHz                                                              1.20-1.50(3H, m)                                                              1.55-2.00(7H, m)                                                              2.51(3H, s)                                                                  2.80(1H, m)                                                                   4.94(2H, brs)                                                                 7.67(2H, d,                                                                   J=8.6Hz)                                                                      7.98(2H, d,                                                                   J=8.6Hz) neat                                                                 3262  2929  2853                                                              1575  1332  1164                                                              FAB+  321(MH.sup.+                                                            ) C.sub.16                                                                    H.sub.20 N.sub.2                                                              O.sub.3 S                                                                     calculated  C                                                                 59.98%  H 6.29%                                                               N 8.74%  found  C                                                             59.99%  H 6.31%                                                               N 8.68%                  - 15                                                                                                                                 140-1143°                                                             C.  white  solid                                                             CDCl.sub.3 300MHz                                                              1.20-1.50(3H, m)                                                              1.60-2.00(7H, m)                                                              2.51(3H, s)                                                                  2.71(3H, d,                                                                   J=5.4Hz)                                                                      2.81(1H, m)                                                                   4.32(1H, q,                                                                   J=5.4Hz)                                                                      7.68(2H, d,                                                                   J=8.7Hz)                                                                      7.91(2H, d,                                                                   J=8.7Hz) neat                                                                 3286  2927  2853                                                              1577  1329  1164                                                              FAB+  335.2(MH.sup                                                            .+) C.sub.17                                                                  H.sub.22 N.sub.2                                                              O.sub.3 S                                                                     calculated  C                                                                 61.05%  H 6.63%                                                               N 8.38%  found  C                                                             61.00%  H 6.74%                                                               N 8.19%               __________________________________________________________________________

EXPERIMENTAL EXAMPLE 1-1 (INHIBITORY ACTIVITY ON CYCLOOXYGENASE)

The enzymatic activity was determined by the percent conversion of ¹⁴ Carachidonic acid into prostaglandin (PG)H₂ and the decomposed products.That is, a test sample (20 μl), an enzyme solution (20 μl) and distilledwater (10 μl) were added to 100 mM Tris-HCl buffer (pH 8, 140 μl)containing hematin (2 μM) and tryptophan (5 mM), and the mixture wasthoroughly stirred, which was followed by preincubation at 24° C. for 5minutes. Then, a ¹⁴ C arachidonic acid solution (10 μl) was added andthe mixture was reacted at 24° C., whereafter a solution (40 μl) ofethyl ether/methanol/1M citric acid (30/4/1) ice-cooled to -20° C. wasadded to stop the reaction. The reaction mixture was centrifuged for 5minutes at 3,000 rpm to give an ether layer which was placed on athin-layer plate, and developed with ethyl ether/methanol/acetic acid(90/2/0.1) to determine percent conversion (A) from arachidonic acid toPGH2 and the decomposed product thereof. The percent conversion (B)without a test sample was also determined, based on which percentinhibition was calculated from the following formula, and aconcentration necessary for 50% inhibition (IC₅₀) of the test sample wasdetermined.

    Inhibition (%) (1-A/B)×100

Sheep seminal vesicle microsome fraction (1 mg/ml, manufactured byCayman Chemical Company) was used as an enzyme solution ofcyclooxygenase-1, and sheep placenta solubilized fraction (4000units/ml, manufactured by Cayman Chemical Company) was used as an enzymesolution of cyclooxygenase-2.

The results are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Experimental Example 1-1                                                        (inhibitory activity on cyclooxygenase)                                                      IC.sub.50 (μM) or % inhibition                            Example          COX-2       COX-1                                            ______________________________________                                         1                5           11%*                                               2(A)  0.4  50                                                                 2(B) 80  10%*                                                                 3 <1  18%*                                                                    4  4  26%*                                                                    5 10   5%*                                                                    6 18%*  50                                                                    7  0.6   2                                                                    8  7%*   7%*                                                                  9 35%*   2%*                                                                 10(A)  0.2  13%*                                                              10(B) 30  57%*                                                                11(A) 50  14%*                                                                11(B)  2%*   6%*                                                              12 16%* >100                                                                  14  1.5 >100                                                                  indomethacin  8   0.5                                                       ______________________________________                                         Note *: inhibition at 100 μM test compound                            

EXAMPLE 1-2 (INHIBITORY ACTIVITY ON CYCLOOXYGENASE)

A test similar to that performed in Experimental Example 1-1 wasconducted wherein an enzyme prepared from human platelets was used as anenzyme solution of cyclooxygenase-1, and an enzyme expressed by a yeast,into which cDNA of human cyclooxygenase-2 had been transfected using akit of Invitrogen Corp., was used as an enzyme solution ofcyclooxygenase-2.

The results are shown in Table 8.

                  TABLE 8                                                         ______________________________________                                        Experimental Example 1-2                                                        (inhibitory activity on cyclooxygenase)                                                      IC.sub.50 (μM)                                            Example          COX-2       COX-1                                            ______________________________________                                         1               0.07        >100                                                2(A) 0.04  47.5                                                               4  >100                                                                       7 0.4 >100                                                                   10(A) 0.03  12.5                                                              13 0.02   0.6                                                                 14 0.07  45                                                                   15 4 >100                                                                     indomethacin 1.5   0.26                                                     ______________________________________                                    

EXPERIMENTAL EXAMPLE 2 (EFFECTS ON CARRAGEENIN-INDUCED PAW EDEMA)

Carrageenin (1%, 0.05 ml) dissolved in physiological saline wassubcutaneously injected to the left hind paw of male Donryu rats toinduce paw edema. The degree of paw edema was evaluated by measuring thevolume of the paw 3 hours after carrageenin administration. A testcompound (1, 3, 10 or 30 mg/kg) was orally administered one hour beforecarrageenin administration, and suppression thereby was studied.Inhibitory activity was expressed by the dose (ED₃₀) of the testcompound necessary for inhibiting by 30% relative to the control group.The results are shown in Table 9.

                  TABLE 9                                                         ______________________________________                                        Experimental Example 2                                                          (effects on carrageenin-induced paw edema in rats)                                            carrageenin-induced paw edema                                 Example in rats, ED.sub.30 (mg/kg p.o.)                                     ______________________________________                                         1            5.4                                                                2(A) 10.8                                                                    10(A) 5.4                                                                     11(A) 9.5                                                                     14 4.5                                                                        indomethacin 2.9                                                            ______________________________________                                    

EXPERIMENTAL EXAMPLE 3 (EFFECTS ON FORMATION OF GASTRIC ULCER)

A test compound (100 mg/kg) was orally administered (10 ml/kg) to maleDonryu rats. Six hours later, the stomach of the rats was exposed andfixed with 0.1% formalin. The stomach was opened and the degree of ulcerformation was evaluated. The results are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                        Experimental Example 3                                                          (effects on gastric ulcer formation in rats)                                                  gastric ulcer formation in                                    Example rats (mg/kg p.o.)                                                   ______________________________________                                         1            >100                                                               2(A) >100                                                                    10(A) >100                                                                    14 >100                                                                       indomethacin 10                                                             ______________________________________                                    

INDUSTRIAL APPLICABILITY

The compound of the present invention and pharmaceutically acceptablesalts thereof have phenyl substituted by methylsulfonyl, aminosulfonylor lower alkylaminosulfonyl at one of the 4- and 5-positions of oxazolering, cycloalkyl optionally substituted by lower alkyl, or thienyl orfuryl, which may be substituted by lower alkyl or halogen atom, at theother position, and lower alkyl at the 2-position thereof, whereby anoxazole derivative having superior antipyretic action, analgesic actionand anti-inflammatory action, and which shows less side-effects such asdisorders in the digestive tract can be obtained.

The selective inhibition of COX-2 by the compound of the presentinvention results in decreased side-effects, such as disorders in thedigestive tract, which have been conventionally observed in the use ofNSAID. Consequently, the compound of the present invention is useful asan antipyretic agent, an analgesic agent and an anti-inflammatory agent,which have not existed heretofore.

In addition, the utility thereof as a therapeutic agent for the diseasespossibly caused by COX-2 product, such as asthma and rheumatism, can beexpected.

What is claimed is:
 1. A method for selectively inhibiting the action ofCOX-2, which comprises administering a pharmaceutically effective amountof an oxazole derivative of the formula (I) ##STR25## wherein R₁ ismethylsulfonylphenyl or an aminosulfonylphenyl, R is a cyclohexyl,5-halo-2-thienyl or 5-methyl-2-thienyl, and R₂ is mehtyl, or apharmaceutically acceptable salt thereof to a patient.
 2. A method fortreating inflammation, which comprises administering a pharmaceuticallyeffective amount of an oxazole derivative of the formula (1)wherein R₁is a methylsulfonylphenyl or an aminosulfonylphenyl, R is a cyclohexyl,5-halo-2-thienyl or 5-methyl-2-thienyl, and R₂ is a methyl, or apharmaceutically acceptable salt thereof to a patient suffering frominflammation.